1. Suppression of PI3K/Akt signaling by synthetic bichalcone analog TSWU-CD4 induces ER stress- and Bax/Bak-mediated apoptosis of cancer cells
- Author
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Tian Shung Wu, Ren Yu Huang, Shih-Shun Chen, Mopuru Vijaya Bhaskar Reddy, Meng Liang Lin, Yao Cheng Lu, Yu Ren Liao, and Chuan Chun Lee
- Subjects
Cancer Research ,Small interfering RNA ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Dantrolene ,Piperazines ,Cell Line ,Phosphatidylinositol 3-Kinases ,eIF-2 Kinase ,Chalcones ,Humans ,Protein kinase A ,Endoplasmic Reticulum Chaperone BiP ,Protein kinase B ,Caspase 12 ,Heat-Shock Proteins ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,bcl-2-Associated X Protein ,Pharmacology ,Kinase ,Chemistry ,Endoplasmic reticulum ,Biochemistry (medical) ,Cell Biology ,Calcium Channel Blockers ,Endoplasmic Reticulum Stress ,Mitochondria ,Cell biology ,bcl-2 Homologous Antagonist-Killer Protein ,Biochemistry ,Unfolded protein response ,Calcium ,Protein Multimerization ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Suppression of the activity of pro-apoptotic Bcl-2-family proteins frequently confers chemoresistance to many human cancer cells. Using subcellular fractionation, the ER calcium (Ca(++)) channel inhibitor dantrolene and small interfering RNA (siRNA) against Bax or Bak, we show that the new synthetic bichalcone analog TSWU-CD4 induces apoptosis in human cancer cells by releasing endoplasmic reticulum (ER)-stored Ca(++) through ER/mitochondrial oligomerization of Bax/Bak. Blockade of the protein kinase RNA-like ER kinase or the unfolded protein response regulator glucose-regulated protein 78 expression by siRNA not only suppressed oligomeric Bax/Bak-mediated pro-caspase-12 cleavage and apoptosis but also resulted in an inhibition of Bcl-2 downregulation induced by TSWU-CD4. Induction of the ER oligomerization of Bax/Bak and apoptosis by TSWU-CD4 were suppressed by Bcl-2 overexpression. Inhibition of lipid raft-associated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling by TSWU-CD4 induced ER stress- and oligomeric Bax/Bak-mediated apoptosis, which were substantially reversed by overexpression of the wt PI3K p85α subunit. Taken together, these results suggest that suppression of lipid raft-associated PI3K/Akt signaling is required for the ER stress-mediated apoptotic activity of Bax/Bak, which is responsible for the ability of TSWU-CD4-treated cancer cells to exit the ER-mitochondrial apoptotic cell death pathway.
- Published
- 2014